rs13079478

Positions:

• chr3-45966331-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024513.4(FYCO1):​c.3003C>A​(p.Asn1001Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,960 control chromosomes in the GnomAD database, including 13,741 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1001E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.088 (971 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12770 hom.)
• Consequence: FYCO1 NM_024513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.322

Genes affected

FYCO1 (HGNC:14673): (FYVE and coiled-coil domain autophagy adaptor 1) The gene encodes a Rab7 adapter protein that is implicated in the microtubule transport of autophagosomes. The encoded protein contains a RUN domain, a FYVE-type zinc finger domain, and Golgi dynamics (GOLD) domain. The encoded protein plays a role in microtubule plus end-directed transport of autophagic vesicles through interactions with the small GTPase Rab7, phosphatidylinositol-3-phosphate (PI3P), the autophagosome marker LC3, and the kinesin KIF5. Mutations in this gene are associated with inclusion body myositis (IBM) and autosomal recessive congenital cataracts (CATC2). [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032511652).
• BP6: Variant 3-45966331-G-T is Benign according to our data. Variant chr3-45966331-G-T is described in ClinVar as [Benign]. Clinvar id is 261729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45966331-G-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYCO1	NM_024513.4	c.3003C>A	p.Asn1001Lys	missense_variant	8/18	ENST00000296137.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYCO1	ENST00000296137.7	c.3003C>A	p.Asn1001Lys	missense_variant	8/18	1	NM_024513.4	P1

Frequencies

GnomAD3 genomes AF: 0.0885 AC: 13468 AN: 152166 Hom.: 972 Cov.: 33

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0908

GnomAD3 exomes AF: 0.124 AC: 31070 AN: 249724 Hom.: 3025 AF XY: 0.139 AC XY: 18806 AN XY: 135120

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.0609

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.00266

Gnomad SAS exome AF: 0.339

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.115 AC: 168149 AN: 1461676 Hom.: 12770 Cov.: 37 AF XY: 0.123 AC XY: 89680 AN XY: 727152

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.0628

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.00204

Gnomad4 SAS exome AF: 0.335

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.0884 AC: 13461 AN: 152284 Hom.: 971 Cov.: 33 AF XY: 0.0944 AC XY: 7029 AN XY: 74464

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.0642

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.0918

Alfa AF: 0.105 Hom.: 1394

Bravo AF: 0.0716

TwinsUK AF: 0.0992 AC: 368

ALSPAC AF: 0.0986 AC: 380

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.126 AC: 15337

Asia WGS AF: 0.169 AC: 588 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.113

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 18 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.97
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.11
Sift	Benign	0.098	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0080	.;B
Vest4		0.025
MutPred		0.25		Gain of ubiquitination at N1001 (P = 0.0022);Gain of ubiquitination at N1001 (P = 0.0022);
MPC		0.19
ClinPred		0.00044	T
GERP RS		1.4
Varity_R		0.066
gMVP		0.067

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs13079478; hg19: chr3-46007823;